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Interaction between HSV-2 and HIV

Interaction between HSV-2 and HIV. Dr Jean-Elie Malkin Centre Médical de l’Institut Pasteur. Genital Herpes: Early AIDS-associated Opportunistic Infection. Co-infection is common. Epidemiological association between HSV and HIV established (Wasserheit, JID 1992)

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Interaction between HSV-2 and HIV

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  1. Interaction between HSV-2 and HIV Dr Jean-Elie Malkin Centre Médical de l’Institut Pasteur

  2. Genital Herpes: Early AIDS-associated Opportunistic Infection

  3. Co-infection is common • Epidemiological association between HSV and HIV established (Wasserheit, JID 1992) • Sero-prevalence of HSV-1 and HSV-2 infection significantly higher in HIV-1 infected persons than in uninfected (Heng et al. Lancet 1994) • But risk of acquisition of HIV and HSV both related to sexual behaviour?

  4. In Africa: • HSV-2 as major factor in differing HIV prevalence in 4 African cities • HSV-2 as increasing proportion of GUD • HSV-2 increases risk of HIV acquisition • 2-fold overall increased risk • 5-fold increase in per-contact risk (Rakai)* • HSV-2 increases risk of HIV transmission • 5-fold increase in per-contact risk due to GUD (Rakai)* Gray RH. Lancet 2001

  5. Yaounde HIV-1: 7% W, 3.6% M HSV-2: 51% W, 27% M Cotonou HIV-1: 2.8% W, 2.8% M HSV-2: 30% W, 12% M Kisumu HIV-1: 29% W, 18% M HSV-2: 68% W 35% M Ndola HIV-1: 32% W, 24% M HSV-2: 55% W, 36% M

  6. Factors related to different HIV prevalence in 4 African cities • Differences in risky sexual behavior are outweighed by co-factors that affect HIV transmission probability: • Lack of male circumcision • HSV-2 infection • Syphilis • With increasing numbers of HSV-2 /HIV co-infected persons, HSV-2 increases transmission of HIV and HSV-2 • HIV and HSV-2 epidemics fuel each other Buve A. AIDS 2001

  7. Etiology of GUD in South Africa (1986-98)Ballard 2001

  8. HSV-2 and HIV acquisition Estimate of risk for 9 cohort and nested case-control studies: 2.1 (1.3, 3.2) Estimate of risk for 18 case-control and cross-sectional studies: 4.2 (3.1, 5.8) Results of meta-analysis: Wald. J Infect Dis 2002

  9. MSM with HSV and risk of HIV acquisition Studied 116 HIV seroconverters and 342 controls of MSM. HIV incidence was 2.3 in MSM who acquired HSV-2 during follow-up, compared with 1.5 per 100 patient years in those who remained HSV-2 sero-negative Renzie C. J Infect Dis 2003

  10. Probability of HIV acquisition in 174 monogamous couples: Rakai HIV acquisition risk per 1000 exposures HSV-2 antibody in HIV- partner Viral load in HIV+ SP <1700 1700-12,499 12,500-38,499 >38,500 HSV-2 Neg 0.04 0.5 0.2 0.7 HSV-2 Pos 1.0 2.3 1.8 3.6

  11. Attributable and population attributable risk % of HIV to HSV-2 • AR% = 51 • If HSV-2 prevalence = 22%, PAR%= 19 • ~ HSV-2 prevalence in general population in USA & Europe • If HSV-2 prevalence = 50%, PAR%= 35 • ~ HSV-2 prevalence in MSM in Latin America, USA • If HSV-2 prevalence = 80%, PAR%= 46 • ~ HSV-2 prevalence in women in Africa

  12. Summary: HSV-2 and HIV acquisition • HSV-2 increases risk of HIV acquisition 2-fold, even in persons with asymptomatic HSV-2 • Hypothesis: Increased HIV susceptibility through portal of entry and recruitment of activated CD4 cells • Concern about unmeasured confounding • Higher risk of HIV acquisition among those with recent HSV-2 infection • Hypothesis: More frequent and longer HSV-2 reactivation • HSV-2 increases HIV set-point after HIV acquisition • Hypothesis: HSV-2 increases HIV replication • HSV-2 may influence HIV disease progression

  13. Proof-of-concept” trials of HSV-2 suppression to reduce HIV acquisition • USA NIH: HIV Prev Trials Network 039: ongoing, HIV- HSV-2+ MSM and women (PI, Celum, co-PI Wald). Ongoing through 2006 • LSHTM and WellcomeTrust: HIV- HSV-2+ women in Mwanza, Tanzania (PI Watson-Jones, co-PI Hayes). Ongoing • CDC/USAID: HIV- HSV-2+ male gold miners in South Africa (PI Ballard). Start-up activities

  14. HPTN 039: Proof-of-concept trial of HSV-2 suppressive therapy to prevent HIV acquisition Harare, Zimbabwe Lusaka, Zambia Johannesburg, SA 1800 HIV- HSV-2+ heterosexual women and 1800 high-risk, HIV- HSV-2+ MSM Lima, Peru Seattle, USA San Francisco, USA New York, USA Randomize Aciclovir 400 mg bid x 1 yr Placebo x 1 yr 1° endpoint: HIV infection (estimated to be 3.5%/yr in placebo arm)

  15. HSV-2 and HIV Transmission Data from Rakai HIV-discordant couples HSV-2 and HIV infectiousness

  16. Effect of HSV-2 suppression on HIV transmission • Rationale: • Rakai observational data of 5-fold increased risk of HIV transmission from GUD on per-contact basis • In vitro data of increased HIV replication during HSV-2 reactivation • Cross-over studies show decreased HIV plasma viral load and mucosal HIV shedding during HSV-2 suppression

  17. HIV-1 DNA in Genital Ulcers days Gadkari. AIDS 1998

  18. Detection of HIV-1 RNA in HSV-2 Lesions • HIV RNA detected in 25/26 episodes • HIV RNA detected on 112/170 (66%) days

  19. Changes in Plasma HIV-1 RNA With HSV Reactivation Mole. J Infect Dis

  20. Effect of Acyclovir

  21. Summary HSV HIV

  22. Potential transmission benefits of HSV-2 suppressive therapy in HIV+ persons • Decreased transmission of HIV • If proof-of-concept trial of HSV-2 suppression in HIV-discordant couples shows efficacy • Decreased transmission of HSV-2 • Would slow the HSV-2 epidemic in high prevalence settings, which may also indirectly lead to lower HIV prevalence

  23. Research needs: Effect of HSV-2 suppression on HIV transmission • HIV shedding during GUD (surrogate data on infectiousness) • HIV shedding (titer and duration) from HIV+ persons with GUD during aciclovir vs placebo (USAID/CDC; ANRS) • HIV shedding during subclinical HSV-2 • HIV/HSV-2 co-infected persons on HAART (Wald) • HIV/HSV-2 co-infected MSM, CD4 >250, no HAART (Sanchez, Celum) • HIV/HSV-2 co-infected women, CD4 >250 (CDC, LSHTM) • Proof-of-concept study: HSV-2 suppression on HIV transmission in HIV-discordant couples(Celum et al)

  24. Episodic treatment of genital herpes: ACV in syndromic management of genital ulcers • Randomised, placebo-controlled, double-blinded, multi-center trial by ANRS • To evaluate anti-herpetic treatment as part of syndromic treatment for genital ulcers in Africa • Impact of syndromic management +/- aciclovir on genital shedding of HIV and of HSV-2

  25. Design of ANRS trial • 600 women presenting with genital ulcers over two years: • Bangui (Central African Republic) • Accra (Ghana) • Syndromic management of genital ulcers • Presumptive antibiotics for chancroid and syphilis • Using national & international guidelines (CDC, UK, WHO) • Plus,randomization to either aciclovir 400 mg 3 times daily for 5 days or placebo • Exam & cervicovaginal samplings at days 0, 3, 7,14 & 30 for: • Etiological diagnosis of ulcers by multiplex PCR • HIV RNA and proviral DNA, and HSV-2 DNA

  26. HSV-2 suppressive therapy to prevent HIV transmission 3646 HIV- discordant couples HSV-2serology & CD4 testing of HIV+ partner Randomize HIV/HSV-2 + persons w/ CD4 > 250 Aciclovir 400 mg bid x 1 yr Placebo x 1 yr 1° endpoint: HIV infection in HIV-negative partners at 1 yr - 90% power to detect 50% reduction; 4% HIV incidence in placebo

  27. Prospective sites for Gates HSV-HIV transmission trial Nairobi, Eldoret, Kisumu, Kenya Kitwe and Ndola, Zambia Kampala, Uganda Moshi, Tanzania Gabarone, Botswana • Other potential sites: • Chennai, India • Port au Prince, Haiti • Harare, Zimbabwe • Capetown, SA Johannesburg, Durban RSA

  28. Options for HSV-2 prevention for HIV prevention • Effective HSV-2 vaccine • Ideally effective in HSV-1 seropositive populations in developing countries where HSV-1, HSV-2 and HIV prevalence rates are high • HSV-2 suppressive therapy • Adherence issues • Cost (generic ACV 400 bid = $40/yr) • Resistance issues • HSV-2 episodic therapy • Anticipate smaller reduction in HIV incidence, given high proportion of HSV-2 that is subclinical, even in HIV+ persons

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